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000163644 1001_ $$0P:(DE-HGF)0$$aLiese, Juliane$$b0
000163644 245__ $$aCotreatment with sorafenib and oleanolic acid induces reactive oxygen species-dependent and mitochondrial-mediated apoptotic cell death in hepatocellular carcinoma cells.
000163644 260__ $$a[S.l.]$$bOvid$$c2019
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000163644 520__ $$aHepatocellular carcinoma (HCC) is the most common liver malignancy, and the lack of effective chemotherapies underlines the need for novel therapeutic approaches for this disease. Recently, we discovered a novel synergistic induction of cell death by combining sorafenib, the only routinely used palliative chemotherapeutic agent, and the triterpenoid oleanolic acid (OA). However, the underlying mechanisms of action have remained obscure. Here, we report that sorafenib and OA acted in concert to trigger mitochondria-mediated apoptotic cell death, which is dependent on reactive oxygen species (ROS). Sorafenib/OA cotreatment significantly increased ROS production, which was prevented by the ROS scavengers α-tocopherol and MnTBAP. Importantly, rescue experiments showed that ROS were required for sorafenib/OA-induced apoptosis as ROS scavengers protected HCC cells against cell death. In addition, sorafenib and OA cotreatment cooperated to decrease myeloid cell leukaemia-1 expression and to activate Bak, two events that were prevented by ROS scavengers. Bak activation was accompanied by the loss of mitochondrial membrane potential, followed by PARP cleavage, DNA fragmentation and, finally, apoptotic cell death in HCC cells. By providing new insights into the molecular regulation of sorafenib/OA-mediated and ROS-dependent cell death, our study contributes toward the development of novel treatment strategies to overcome sorafenib resistance in HCC.
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000163644 650_7 $$2NLM Chemicals$$aAntineoplastic Agents
000163644 650_7 $$2NLM Chemicals$$aReactive Oxygen Species
000163644 650_7 $$06SMK8R7TGJ$$2NLM Chemicals$$aOleanolic Acid
000163644 650_7 $$09ZOQ3TZI87$$2NLM Chemicals$$aSorafenib
000163644 650_2 $$2MeSH$$aAntineoplastic Agents: pharmacology
000163644 650_2 $$2MeSH$$aApoptosis
000163644 650_2 $$2MeSH$$aCarcinoma, Hepatocellular: drug therapy
000163644 650_2 $$2MeSH$$aCarcinoma, Hepatocellular: metabolism
000163644 650_2 $$2MeSH$$aCarcinoma, Hepatocellular: pathology
000163644 650_2 $$2MeSH$$aCell Proliferation
000163644 650_2 $$2MeSH$$aDrug Therapy, Combination
000163644 650_2 $$2MeSH$$aHumans
000163644 650_2 $$2MeSH$$aLiver Neoplasms: drug therapy
000163644 650_2 $$2MeSH$$aLiver Neoplasms: metabolism
000163644 650_2 $$2MeSH$$aLiver Neoplasms: pathology
000163644 650_2 $$2MeSH$$aMembrane Potential, Mitochondrial: drug effects
000163644 650_2 $$2MeSH$$aMitochondria: drug effects
000163644 650_2 $$2MeSH$$aMitochondria: metabolism
000163644 650_2 $$2MeSH$$aMitochondria: pathology
000163644 650_2 $$2MeSH$$aOleanolic Acid: pharmacology
000163644 650_2 $$2MeSH$$aReactive Oxygen Species: metabolism
000163644 650_2 $$2MeSH$$aSorafenib: pharmacology
000163644 650_2 $$2MeSH$$aTumor Cells, Cultured
000163644 7001_ $$aHinrichs, Tobias M$$b1
000163644 7001_ $$aLange, Matthias$$b2
000163644 7001_ $$0P:(DE-HGF)0$$aFulda, Simone$$b3
000163644 773__ $$0PERI:(DE-600)2025803-3$$a10.1097/CAD.0000000000000750$$gVol. 30, no. 3, p. 209 - 217$$n3$$p209 - 217$$tAnti-cancer drugs$$v30$$x0959-4973$$y2019
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